Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
  • C07D317/20—Free hydroxyl or mercaptan
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
  • C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified

Definitions

• the present invention relates to a process for preparation of 1,3-dioxolane-4-methanol compounds useful as an intermediate of medicines, agricultural chemicals, etc.
• 1,3-Dioxolane-4-methanol compounds are used as an intermediate of medicines, agricultural chemicals, etc. and following processes for preparation of them are known: (i) A process for preparation of them by reacting glycerin and an acetonide reagent (Synth. Commun., 22, 2653(1992), (ii) a process for preparation of them from mannitol (Biochem. Prep., 2, 31(1952)), (iii) a process for preparation of them from an ascorbic acid (J. Am. Chem. Soc., 102, 6304(1980), (iv) a process for preparation of them from serine (Japanese Patent Publication B No. 6-62492), (v) an optical resolution of them by using an enzyme (J. Chem. Soc., Perkin Trans. I 23, 3459(1994) and so on.
• the present inventors engaged extensively in solving above problems, and found a novel process for preparing the above objective compound from a 3-halogeno-1,2-propanediol.
• the present invention relates to a process for preparing a 1,3-dioxolane-4-methanol compound of the formula ##STR2## wherein R 1 and R 2 are the same or different and are hydrogen atom, alkyl having 1 to 4 carbon atoms or phenyl, and R 1 and R 2 may form a cycloalkyl ring having 3 to 6 carbon atoms with the adjacent carbon atoms, which is characterized in acetalizing a 3-halogeno-1,2-propanediol of the formula ##STR3## wherein X is halogen atom, with an acetalizing agent in the presence of an acid catalyst to prepare a 4-halogenomethyl-1,3-dioxolane of the formula ##STR4## wherein R 1 , R 2 and X are as defined above, and reacting it with an alkali metal salt or alkaline earth metal salt of a carboxylic acid or an alcohol of the formula
• R is acyl, aralkyl or allyl, to prepare a compound of the formula ##STR5## wherein R, R 1 and R 2 are as defined above, and when R is acyl in the formula (4), subjecting it to hydrolysis, and when R is aralkyl or allyl in the formula (4) subjecting it to hydrogenolysis in the presence of a reduction catalyst.
• an optically active 3-halogeno-1,2-propanediol as a starting material, there is obtained an optically active 1,3-dioxolane-4-methanol compound.
• a 4-halogenomethyl-1,3-dioxolane of the formula (2) is obtained by reacting a 3-halogeno-1,2-propanediol of the formula (1) with an acetalizing agent in the presence of an acid catalyst.
• 3-halogeno-1,2-propanediols are 3-chloro-1,2-propanediol and 3-bromo-1,2-propanediol.
• acetalizing agents examples include ketones, such as acetone, diethyl ketone, benzophenone, cyclohexanone, etc., aldehydes, such as formaldehyde, acetoaldehyde, benzaldehyde, etc., dialkoxyacetals of ketones, such as 2,2-dimethoxypropane, 2,2-dimethoxypentane, etc., enol ethers of ketones, such as 2-methoxypropene etc. and so on.
• ketones such as acetone, diethyl ketone, benzophenone, cyclohexanone, etc.
• aldehydes such as formaldehyde, acetoaldehyde, benzaldehyde, etc.
• dialkoxyacetals of ketones such as 2,2-dimethoxypropane, 2,2-dimethoxypentane, etc.
• enol ethers of ketones such as 2-
• the examples of the acid catalysts are organic acids, such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate, camphorsulfonic acid, etc., mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., and Lewis acid, such as, trifluoroborate etc.
• the amount of the acid catalyst is 0.05 to 0.1 mol equivalent to a 3-halogeno-1,2-propanediol.
• solvents are ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc., halogen compounds, such as dichloromethane, dichloroethane, etc., acetone and so on.
• the reaction temperature is from 0° C. to refluxing temperature of the solvent.
• Step(B) (B-1) A 4-acyloxymethyl-1,3-dioxolane of the formula (4) in which R is acyl, is prepared by reacting a 4-halogenomethyl-1,3-dioxolane of the formula (2) which is prepared by step (A) with an alkali metal salt or alkaline earth metal salt of a carboxylic acid.
• solvents are polar aprotic solvents, such as N,N-dimethylformamide, dimethyl sulfoxide etc., esters, such as ethyl acetate, butyl acetate, etc., ethers, such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme, diethlene glycol monomethyl ether, etc., ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc., nitriles, such as acetonitrile etc., halogen compounds, such as dichloromethane, 1,2-dichloroethane, etc., water and a mixture of these solvents.
• polar aprotic solvents such as N,N-dimethylformamide, dimethyl sulfoxide etc.
• esters such as ethyl acetate, butyl a
• alkali metal salts or alkaline earth metal salts of a carboxylic acid are salts of an aliphatic carboxylic acid having 1 to 4 carbon atoms, salts of an aromatic carboxylic acid substituted or unsubstituted by an alkyl having 1 to 4 carbon atoms, nitro, cyano, a halogen atom, or an alkoxy having 1 to 4 hydrocarbon.
• the carboxylates are alkali metal salts or alkaline earth metal salts of benzoic acid and acetic acid, such as sodium benzoate, potassium benzoate, sodium acetate, potassium acetate, calcium benzoate, barium benzoate, etc.
• the amount of the alkali metal salt or alkaline earth metal salt of a carboxylic acid is 1 to 3 moles per one mole of a 4-halogenomethyl-1,3-dioxolane, preferably 1 to 2 moles. To use it in excess does not affect the yield of the product, but it is not economical.
• (B-2) A 4-alkoxymethyl-1,3-dioxolane of the formula (4) in which R is aralkyl or allyl, is prepared by reacting a 4-halogenomethyl-1,3-dioxolane of the formula (2) which is prepared by step (A) with an alkali metal salt or alkaline earth metal salt of an alcohol.
• Examples of the alcohols are ones having aralkyl group or allyl group, especially preferably benzyl alcohol and allyl alcohol.
• the amount of the alcohol is 1 to 4 mole equivalent to a 4-halogenomethyl-1,3-dioxolane.
• Examples of bases used in preparing the alkali metal salt or alkaline earth metal salt of an alcohol are alkali metal or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, calcium carbonate, etc., alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc., alkali metal or alkaline earth metal hydrides, such as sodium hydride, lithium hydride, calcium hydride, etc., preferably alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, alkali metal or alkaline earth metal hydrides, such as sodium hydride, lithium hydride and calcium hydride.
• solvents examples include polar aprotic solvents, such as N,N-dimethylformamide, dimethyl sulfoxide, etc., ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc., halogen compounds, such as dichloromethane, 1,2-dichloroethane, etc., water and a mixture of these solvents.
• polar aprotic solvents such as N,N-dimethylformamide, dimethyl sulfoxide, etc.
• ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.
• halogen compounds such as dichloromethane, 1,2-dichloroethane, etc.
• the alcohols used as a starting material may serve as a solvent by using in excess.
• steps (B-1) and (B-2) proceed without catalyst, but the reactions are accelerated by adding iodo compounds, such as cesium iodide, sodium iodide, potassium iodide, etc., bromo compounds such as cesium bromide, sodium bromide, potassium bromide, etc., quaternary ammonium phase transfer salts such as terabutylammonium chloride, trimethylammonium bromide, etc., crown ether such as 18-Crown-6 etc., especially effective in case of a halogen atom in the formula (2) being chlorine atom.
• iodo compounds such as cesium iodide, sodium iodide, potassium iodide, etc.
• bromo compounds such as cesium bromide, sodium bromide, potassium bromide, etc.
• quaternary ammonium phase transfer salts such as terabutylammonium chloride, trimethylammonium bromide, etc.
• the preferable reaction promoters are an alkali metal bromide and an alkali metal iodide, especially sodium bromide, potassium bromide, sodium iodide and potassium iodide. Its amount is 0.05 to 1.1 mole equivalent to a 4-halogenomethyl-1,3-dioxolane. The reaction rate decreases in less than the amount and it is not practical.
• a 1,3-dioxolane-4-methanol compound of the formula (5) is obtained by hydrolysis of a 4-acyloxymethyl-1,3-dioxolane of the formula (4) prepared by the above step (B-1) with a base in a solvent.
• solvents examples include alcohols such as methanol, ethanol, propanol, butanol, etc., ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc., water and a mixture of these solvents.
• bases are alkali metal or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, calcium carbonate, etc., alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc.
• the amount of the base is 1 to 3 mole equivalent to a 4-acyloxymethyl-1,3-dioxolane, preferably 1 to 1.5 mole equivalent.
• the reaction temperature is from 0° C. to refluxing temperature of the solvent.
• a 1,3-dioxolane-4-methanol compound is obtained by catalytic hydrogenolysis of an 4-alkoxymethyl-1,3-dioxolane of the formula (4) prepared by the above step (B-2) under an atmosphere of hydrogen in a solvent.
• the examples of the solvents are esters such as ethyl acetate, butyl acetate, etc., ethers, such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc., ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc., alcohols such as methanol, ethanol, propanol, butanol, etc., water and a mixture of these solvents.
• esters such as ethyl acetate, butyl acetate, etc.
• ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.
• ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.
• alcohols such as methanol, ethanol, propanol, butanol
• the catalysts are not limited as far as catalysts used in this field, but preferable ones are metal catalysts such as palladium, platinum, etc., and palladium is more preferable in view of the yield and economy. Especially about 5-10% palladium-carbon powder is better.
• the amount of the catalyst is preferably 0.5 to 50 weight percent per 4-alkoxymethyl-1,3-dioxolane. The reaction is usually carried out at room temperature under the atmosphere.
• 1,3-dioxolane-4-methanol compound is prepared in good yield and high purity by usual purification methods, such as distillation in vacuo.
• Examples 1 to 5, 7 and 6 are cases in variation of the halogen atoms (examples 1-5, 7: Cl, example 6: Br).
• Examples 1, 3, 5, 6, 2 and 4 are cases in variation of the carboxylates (example 1, 3, 5, 6: sodium benzoate, example 2, 4: sodium acetate).
• Examples 3, 4, 5 and 7 are cases used optically active 3-halogeno-1,2propanediols starting material.
• Example 1 and 5 are cases of a reaction being carried out with or without a reaction promoter.
• Example 7 is a case of using an metal salt of an alcohol.
• sodium bromide (24.70 g, 0.24 mol) and sodium benzoate (34.58 g, 0.42 mol) were added to a mixture of (R)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane (36.48 g, 0.24 mol) and N,N-dimethylformamide (150 ml) and the resulting mixture was stirred for 15 hours at 150° C. After cooling the salt was filtered off and N,N-dimethylformamide was removed in vacuo and water was added to the residue and extracted with toluene.
• sodium benzoate 50.44 g, 0.35 mol
• 4-bromomethyl-2,2-dimethyl-1,3-dioxolane 58.52 g, 0.3 mol
• N,N-dimethylformamide 500 ml
• the salt was filtered and N,N-dimethylformamide was removed in vacuo and water was added to the residue and extracted with toluene.
• 1,3-dioxolane-4-methanol compounds are simply and economically prepared without expense reagents.
• a racemic or optically active compound of 1,3-dioxolane-4-methanol compounds is, if desired, prepared with high purity and in good yield.

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• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)

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• 1997
  • 1997-09-09 JP JP51348598A patent/JP3822644B2/ja not_active Expired - Fee Related
  • 1997-09-09 EP EP97939227A patent/EP0930311B1/de not_active Expired - Lifetime
  • 1997-09-09 TW TW086112992A patent/TW420673B/zh active
  • 1997-09-09 US US09/242,059 patent/US6143908A/en not_active Expired - Fee Related
  • 1997-09-09 AU AU41365/97A patent/AU4136597A/en not_active Abandoned
  • 1997-09-09 WO PCT/JP1997/003165 patent/WO1998011087A1/ja active IP Right Grant
  • 1997-09-09 DE DE69726441T patent/DE69726441D1/de not_active Expired - Lifetime

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